In-111 WBC scintigraphy supplemented by visual comparison with concurrent Tc-99m SC bone marrow imaging is used to identify infection within the marrow-containing skeleton. This retrospective study demonstrates the value of the computer-generated WBC/SC bone marrow subtraction image. Thirty-one patients with various conditions (postsurgery with or without orthopedic hardware, bacteremia with persistent fever, joint arthroplasty, and miscellaneous) underwent combined WBC/SC with bone marrow subtraction imaging. Infection was present in 21 of 36 possible sites (14 osseous, 7 soft tissue; 8 acute, 13 chronic). The bone marrow subtraction image identified two of these sites, which were not appreciated by visual inspection. The sensitivity, specificity, and accuracy for bone marrow subtraction were 95%, 93%, and 94%, respectively, as compared to 86%, 93%, and 89%, respectively, for the visual assessment of WBC and SC images. Computer-assisted subtraction imaging improves overall accuracy and enhances diagnostic certainty of combined WBC/SC scintigraphy for infection in the marrow-containing skeleton.